CA2443089C

CA2443089C - Antifungal suspension of micronized posaconazole

Info

Publication number: CA2443089C
Application number: CA2443089A
Authority: CA
Inventors: Stefan Sharpe; Joel Sequeira; David Harris; Shashank Mahashabde
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2001-04-03
Filing date: 2002-04-01
Publication date: 2011-11-01
Anticipated expiration: 2022-04-01
Also published as: PL212985B1; CN1499930A; EP1372394A1; ZA200307684B; AU2002257104B2; CA2443089A1; AR033096A1; KR20030087052A; US8263600B2; EP2090165A3; JP2008120836A; KR100607742B1; WO2002080678A1; TWI311464B; US20110244004A1; MXPA03009021A; CN100415234C; BR0208626A; HUP0400856A3; US20030055067A1

Abstract

A liquid suspension comprising an antifungally effective amount of the micronized compound represented by the chemical structural formula (I) at least one thickening agent, a non-ionic surfactant, and a pharmaceutically acceptable liquid carrier is disclosed.

Description

ANTIFUNGAL SUSPENSION OF MICRONIZED POSACONAZOLE
BACKGROUND OF THE INVENTION

This invention relates to stable, liquid suspensions containing an antifungally effective amount of the micronized compound represented by the chemical structural formula I:

H& /\ N N \ ! N N S

N
HO
F R O
N
F ~=N

at least one thickening agent, a non-ionic surfactant, and a pharmaceutically acceptable liquid carrier, and methods of using the suspensions to treat or prevent fungal infections U.S. Patent No. 5,661,151 discloses the compound of formula I and its potent antifungal activity against a broad range of fungi such as Aspergillis, Candida, Cryptococcus, Fusarium, and other opportunistic fungi.

U.S. Patent Nos. 5,834,472 and 5,846,971, disclose oral pharmaceutical capsule compositions of the compound of structural formula I coated onto inert beads together with a binder. However, the compound of structural formula I is highly lipophilic, and has an extremely low water solubility. Thus, aqueous compositions of the compound of structural formula I were found to have reduced anti-fungal activity and/or bioavailability, presumably due to the extremely low water solubility of the compound. Accordingly, a need exists for an oral pharmaceutical composition of the compound of structural formula I that has enhanced bioavailability and improved stability characteristics SUMMARY OF THE INVENTION

We have found pharmaceutical compositions, in the form of liquid suspension, suitable for oral administration comprising micronized particles of posaconazole, the compound having the chemical structural formula I

F F H ~\\\O NN NN (S) N H\`, OH
(R) N-N

N

at least one thickening agent, a non-ionic surfactant, and a pharmaceutically acceptable liquid carrier that provides significant advantages over the prior art.
Advantages of the liquid suspensions of the present invention include improved homogeneity of the suspension and ease of dispersibility of the suspension. The solids that settle in the liquid suspension of the present invention do not form a solid cake that is difficult to re-disperse. There is virtually no sedimentation of the solids in the unreconstituted liquid suspension of this invention for a period of at least three days. This surprising feature ensures that a patient having a fungal infection taking the liquid suspensions of the present invention will receive an antifungally effective amount of posaconazole. The liquid suspensions of the present invention have a longer shelf life. Additionally, the liquid suspension, upon reconstitution, provide substantially the same antifungally effective amount posaconazole as the initially prepared suspension. These features of the liquid suspensions of the present invention provide benefits to pharmacies, pharmacists, doctors and patients having fungal infections.
Accordingly, the present invention provides a liquid suspension comprising micronized posaconazole, having the chemical structural formula I:

o H
F ~ F '~\\\ O NN N N (S) I N HS OH
(R) N~\-N

N
at least one thickening agent, a non-ionic surfactant, and a pharmaceutically acceptable liquid carrier.

This invention also provides a liquid suspension comprising an antifungally effective amount of micronized posaconazole having the chemical structural formula I:

H
F F O NN N N (S) S OH
(R) N

N-N

N
an effective amount of at least one thickening agent, an amount of a buffer system effective to maintain the pH of the system in the range of about 4.0 to about 6.0, an effective amount of a non-ionic surfactant, and a pharmaceutically acceptable liquid carrier.

This invention further provides a liquid suspension comprising an antifungally effective amount of micronized posaconazole having the chemical structural formula I:

H O
F O~v F 0 N N NN (S) 3--- N H``OH
(R) N-N I

N

wherein the micronized compound has a mean particle size in the range of about 1200 nm to about 1600 nm, an effective amount of polyoxyethylene derivatives of sorbitan esters of saturated or unsaturated C12 to C18 acids, an effective amount of a buffer system sufficient to maintain a pH in the range of about 4.0 to about 6.0, an effective amount of a combination of two thickening agents, wherein one is a liquid sugar, and a pharmaceutically acceptable liquid carrier.

5 In accordance with one aspect of the present invention there is provided a liquid suspension comprising an antifungally effective amount of the micronized compound represented by the chemical structural formula I:

F F H O NN N N (S) N H\`\7 S OH
(R) N - N

N
wherein the micronized compound of formula I has a mean particle size of about 1000 nm to about 1800 nm, and a pharmaceutically acceptable liquid carrier.

In accordance with another aspect of the present invention there is provided a liquid suspension comprising:

= an antifungally effective amount of the micronized compound represented by the chemical structural formula I:

x F F H O NN N / \ N (S) N S OH
(R) N - N

N

5a = wherein the micronized compound of formula I has a mean particle size in the range of about 1000 nm to about 1800 nm;

= a polyoxyethylene derivative of sorbitan esters of saturated or unsaturated C12 to C18 acids;

= an effective amount of a buffer system sufficient to maintain a pH in the range of about 4.0 to about 6.0;

= a combination of two thickening agents, wherein one is a liquid sugar;
and a pharmaceutically acceptable liquid carrier.

In accordance with another aspect of the present invention there is provided a composition for at least one of treating and preventing a fungal infection in a patient, the composition in the form of a liquid, oral suspension comprising an antifungally effective amount of a micronized compound of the chemical structural formula I:

H O
F 6(R)N N NN (S) N S OH

N-N I

N

wherein the micronized compound of formula I has a mean particle size of 1000 nm to 1800 nm, and the composition comprises at least one thickening agent, at least one non-ionic surfactant, and a pharmaceutically acceptable liquid carrier, and is adapted to provide a maximum concentration (Cmax) of posaconazole in the plasma serum that is 2.5 to 4 times greater when administered with a high-fat meal or a non-fat meal as compared to when administered following a 10 hr fast.

5b In accordance with yet another aspect of the present invention there is provided a use of micronized particles of the compound of formula I

H O
F ..\\\O \ \/ /\ N~N (s) I v N H~\\\ S OH
(R) N-N I

\\N~

in the manufacture of a medicament in the form of a liquid, oral suspension for at least one of treating and preventing a fungal infection in a patient comprising an antifungally effective amount of the compound of formula I, wherein the medicament comprises at least one thickening agent, and least one, surfactant and a pharmaceutically acceptable liquid carrier, wherein the micronized compound of formula I has a mean particle size of about 1000 nm to about 1800 nm.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. I & 2 graphically display the mean plasma concentration time profiles of posaconazole tablets and of the liquid suspension of Example 1 of the present invention. FIG. 1 is a linear:linear graphic profile of the plasma concentration (ng/ml)of the compound of formula I versus time (hours) after administration of the following four Treatments A- D: a single of 2×100 mg of the compound of formula I in the tablet co-precipitate formulation of U.S.
Pat.
No. 5,834,472 with a standardized high-fat breakfast- Treatment D and.
Symbol -.-; a 200 mg of the compound of formula I in the oral suspension of this invention (5 ml) following a 10-hr. fast -Treatment A and. symbol -O-;a 200 mg of the compound of formula I in the oral suspension of this invention (5 ml) with a standardized high-fat breakfast-Treatment B and. symbol -d-;and a 200 mg of 5c the compound of formula I in the oral suspension of this invention (5 ml) with a standardized non-fat breakfast-Treatment C and. symbol-D-.

FIG. 2 is a log linear graphic profile of the plasma concentration (ng/ml)of the compound of formula I versus time in hours for the data presented in FIG.
1.
DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable suspension of micronized particles of the antifungal compound posaconazole in a pharmaceutically acceptable liquid carrier. The suspension of the present invention is stable to settling without sedimentation when stored undisturbed for more than three days at 25 C. (See Table 1 below).

Table 2 below shows that the liquid suspension formulations of this invention are stable in that the concentration of posaconazole in the suspension is substantially the same ( 2%) compared to the initial concentration (as measured by HPLC) for periods of up to 12 months.

We have also found that the stable suspension of the present invention has a remarkably higher (23-36% increase) bioavailability compared to an optimized io oral tablet of micronized particles of posaconazole when each is administered to subjects concurrently with a high fat breakfast. See Tables 3 and 4 and Figures 1 &2 One aspect of the present invention is to provide a pharmaceutical composition that contains micronized particles of posaconazole in combination with a non-ionic surfactant, such as a sorbitan ester and at least one thickening agent, preferably a combination of xanthan gum and a liquid sugar, that are easily dispersible in a pharmaceutically acceptable liquid carrier such as purified water.
The pharmaceutical composition provides a stabilized suspension that does not settle for at least three days, thus ensuring that patients will get an effective dose of posaconazole. Another feature of the stabilized suspension of the present invention is that it is useful in treating patients with HIV-1 infections with oral thrush without posaconazole precipitating out of solution. Another aspect of the present invention is that the suspension of the present invention avoids formation of solid cakes which are difficult to disperse.

The compound of formula I used in the suspensions of the present invention is available from Schering Corporation, Kenilworth, New Jersey , and has been prepared according to Examples 24 and 32 of U.S. Patent No. 5,661,151 and WO
95/17407.

Micron-sized particles of posaconazole preferably have a mean particle size range of about 1000 nanometers (nm) to about 1800 nm, preferably about 1200 nm to about 1600 nm, and most preferably about 1400 nm. This particle size can be io obtained either by the final step during the manufacture of the antifungal compound of formula I or by the use of conventional micronizing techniques after the conventional crystallization procedure(s).

The preferred micronizing technique that is employed to micronize the posaconazole to the desired mean particle size range is microfluidization.

Microfluidization is an alternative to traditional homogenization that utilizes the collision of two product streams at high pressures to produce a much more uniform particle size distribution (according to Microfluidics International Co.) and smaller average particle size of about 1200 nm to 1600 nm. The process and equipment used in microfluidization are described in U.S. Pat. No. 4,533,254.

The micronized posaconazole of the present invention may also be present in crystalline form. It is preferably substantially chemically and optically pure, and it contains less than about 10 % of its optical isomers, enantiomers or other diastereomers. It may be 99% of the optically pure the levorotatory or dextrarotatory isomer. This optically pure compound of chemical structure I
should avoid many of the untoward side effects of a mixture of other optical isomers.
Posaconazole liquid suspension is employed in the composition in antifungally amounts effective to control the fungi of interest. Such antifungally effective amounts can range from about 10 mg/ml to about 100 mg/ml concentration of the liquid suspension formulations of the present invention, more preferably from about 20 mg/ml to about 60 mg/ml, and most preferably about 40 mg/ml of the compound of formula I.

The present invention also provides for a method of treating and/or io preventing fungal infection in a mammal comprising administering to the mammal an amount of the liquid suspension containing the micronized posaconazole in an amount effective for treating and/or preventing such fungal infection.
Antifungally effective amounts of liquid suspensions of present invention containing 40 mg/ml of the compound of formula I is administered orally in the doses of 5 ml -containing 200 mg of formula I - three times a day (TID) or four times a day (QID)- or 10 ml-containing 400 mg of the compound of formula 1-twice a day (BID). Of course, the attending clinician may change the dose and dosing regimen in view of the age, health, and sex of the patient as well as the severity of the fungal infection.

The following terms are used to describe the present pharmaceutical compositions, ingredients that may be employed in its formulation and methods for assessing the compound's bioactivity or bioavailability.

Non-ionic surfactant refers to a surfactant which lacks a net ionic charge and does not dissociate to an appreciable extent in aqueous media. The properties of non-ionic surfactants are largely dependent upon the proportions of the hydrophilic and hydrophobic groups in the molecule. Hydrophilic groups include the oxyethylene group (-OCH2CH2-) and the hydroxy group. By varying the number of these groups in a hydrophobic molecule, such as an ester of a fatty acid, substances are obtained which range from strongly hydrophobic and water insoluble compounds, such as glyceryl monostearate, to strongly hydrophilic and water-soluble compounds, such as the macrogols. Between these two extremes types include those in which the proportions of the hydrophilic and hydrophobic groups are more evenly balanced, such as the macrogol esters and ethers and sorbitan derivatives. Suitable non-ionic surfactants may be found in Martindale, The io Extra Pharmacopoeia, 28th Edition, 1982, The Pharmaceutical Press, London, Great Britain, pp. 370 to 379.

Such suitable non-ionic surfactants include block copolymers of ethylene oxide and propylene oxide, glycol or glyceryl esters of saturated or unsaturated C8 to C20 acids, preferably, polyoxyethylene esters of saturated or unsaturated C8 to C20 acids, polyoxyethylene ethers of saturated or unsaturated C8to C20 acids, and polyvinyl alcohols or sorbitan esters of saturated or unsaturated C10 to C20 acids.
Preferably, the non-ionic surfactant is a sorbitan ester of a saturated or unsaturated C10 to C20 acid, and more preferably the sorbitan ester is a fatty acid ester of sorbitan selected from sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate and sorbitan tristearate, or mixtures thereof.

Suitable sorbitan esters include, e.g. Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, Polysorbate 85, Sorbitan Monolaurate, Sorbitan Mono-oleate, Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Sesquioleate, Sorbitan Trioleate and Sorbitan Tristearate.
The most preferred non-ionic surfactant is Polysorbate 80, available from ICI
Americas under the tradename Tween 80 which is a mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, 5 condensed with approximately 20 moles of ethylene oxide.

Suitable block copolymers of ethylene oxide and propylene oxide generically called "Poloxamers" and include those represented by the following chemical structure I:

HO(CH2CH2O)a(CH2CHO)b(CH2CH2O)aH
1o wherein a is an integer ranging from about 10 to about 110, preferably from about 12 to 101; more preferably from about 12 to 80; and b is an integer ranging from about 20 to about 60, more preferably from about 20 to about 56; also from about 20 to 27.

Suitable glycol and glyceryl esters of fatty acids include glyceryl monooleate 1s and similar water soluble derivatives;

Suitable polyoxyethylene esters of fatty acids (macrogol esters) include polyoxyethylene castor oil and hydrogenated castor oil derivatives;

Suitable polyoxyethylene ethers of fatty acids (macrogol ethers) include Cetomacrogel 1000, Lauromacrogols (a series of lauryl ethers of macrogols of differing chain lengths), e.g. Laureth 4, Laureth 9 and Lauromacrogol 400.

The effective amount of non-ionic surfactant in the composition can range from about 5 mg/ml to about 50 mg/ml concentration of the formulation, more preferably from about 5 mg/mI to about 25 mg/ml, and most preferably 10 mg/ml.

Thickening agents found suitable in the present invention include any commercially available agent useful for such purpose. Xanthan gum, liquid sugars, starches, celluloses and mixtures thereof are preferred thickening agents.
More preferred is a combination of xanthan gum and a liquid sugar and, most preferred is a combination of xanthan gum, NF and glucose, NF. Preferably, the xanthan gum is present in an amount of about 1 mg/ml to about 5 mg/ml, and more preferably the xanthan gum is present in an amount of about 3 mg/ml. Preferably, the glucose NF
is present in an amount of about 200 to about 500 mg/ml, and more preferably about 350 mg/ml. The effective amount of thickening agent of the present invention 1o may be about 1 to about 500 mg/ml, more preferably about 200 to about 500 mg/ml, most preferably about 353 mg/ml. The thickening agents of the present invention facilitate suspension of the formulation after constitution with minimum agitation and prevent rapid settling and caking of the suspension over time.

Pharmaceutically acceptable carriers include those well known in the art, including purified water USP, liquid glucose, NF, and anhydrous glycerol. Most preferred is purified water USP and liquid glucose, NF. The pharmaceutically acceptable carrier may be present in an amount of about 10 to about 500 mg/ml, more preferably about 200 mg/ml to about 400 mg/ml, most preferably about 350 mg/ml.

The buffer systems suitable for the formulations of the present invention are those which maintain the pH of the liquid suspension in the range of about 4 to about 6, preferably in the 4.5 to 5.0, and most preferably about 4.5. The use of a buffer system of sodium citrate, USP and citric acid, USP, is preferred. Other suitable buffer systems may be used to maintain the desired pH range of 4 to 6.

The buffering agents may be present in a concentration of about 0.4 to about 1.5 mg/ml, more preferably about 0.7 to about 1.5 mg/ml, most preferably about 1.1 mg/ml.

Anti-foaming agents found suitable in the present invention include any commercially available agent useful for such purpose including the methylated linear siloxsane polymers end blocked with trimethylsiloxyl units such as dimethicone and simethicone, as well as mixtures of dimethicone with an average chain length of 200 to 250 dimethylsiloxane units and silica gel. The effective amount of anti-foaming agents is an amount sufficient to provide a concentration of 1o about 2 mg/ml to about 4 mg/ml, preferably about 3 mg/ml.

The water soluble preservatives found useful in present invention include sodium benzoate, sodium citrate and benzalkonium chloride as well as other pharmaceutically acceptable water soluble preservatives. Use of sodium benzoate as a preservative is preferred. The effective amount of the water soluble preservative is an amount sufficient to provide a concentration of about 0.5 mg/ml to about 3 mg/ml, most preferably about 2 mg/ml.

The opacifier agents found suitable in the present invention include pharmaceutically acceptable metal oxides, especially titanium dioxide. The effective amount of the opacifier agent is an amount sufficient to provide a concentration of about 2 mg/ml to about 6 mg/ml, most preferably about 4 mg/ml.
Typical flavoring agents are those that are approved by FDA for use in sweetened pharmaceuticals, foods, candies, beverages and the like; these materials impart flavors such as grape, cherry, citrus, peach, strawberry, bubble gum, peppermint and many others. The effective amount of the flavoring agents is an amount sufficient to provide a concentration of about 0.01 mg/ml to about 6 mg/ml, more preferably about 5 mg/ml.

The following examples describe compositions of the present invention containing posaconazole, but they are not to be interpreted as limiting the scope of the claims.

Ingredient Concentration Range (mg/ml) Posaconazole (micronized) 10-100 Polysorbate 80 5-50 Sodium Citrate, USP, 0.4-0.8 Monohydrate Citric Acid, USP, Monohydrate 0.36-0.6 Simethicone, USP 2-4 Xanthan Gum, NF 1-5 Sodium Benzoate, NF 0.5-3 Liquid Glucose, NF 200-500 Glycerin, USP 50-150 Artificial Cherry Flavor 2-10 Titanium Dioxide 2-6 Purified Water, USP q.s. ad ---The above ranges of ingredients may be varied as is evident to one skilled in the art.

Specific examples of a composition within the scope of the invention is set forth below.

Example 1 Ingredient Concentration (mg/ml) Posaconazole 40 (micronized) Polysorbate 80 10 Sodium Citrate, USP, 0.6 Monohydrate Citric Acid, USP, 0.48 Monohydrate Simethicone, USP 3 Xanthan Gum, NF 3 Sodium Benzoate, NF 2 Liquid Glucose, NF 350 Glycerin, USP 100 Artificial Cherry Flavor 5 Titanium Dioxide 4 Purified Water, USP q.s. 1 ml ad This example is prepared as follows: charge approximately 5% of the final batch volume of purified water at 20 3 C to a suitable vessel equipped with a mixer propeller. Add 40% of the polysorbate 80 to the purified water in step 1 and mix until dissolved. Add 40% of the simethicone and mix until it is dispersed.

5 Recirculate the mixture in step 3 through a Microfluidizer, operating at about 30,000 5000 psi for approximately 5 passes. Add approximately 7% of the final batch volume of purified water at about 20 3 C, and mix for approximately five minutes.
Add the Posaconazole to the vessel in step 5 with constant mixing. Continue mixing until it is fully dispersed. Recirculate the suspension portion from step 6 1o through a Microfluidizer, operating at a pressure of about 30,000 5,000 psi.
Process the concentrate until the median of the particles shows a particle size of about 1.4 0.2 pm, when measured via laser diffraction techniques that are known in the art.

When the particle size has been achieved, pass the suspension through the 15 microfluidizer and collect in a suitable sized vessel. Add approximately 8-10% of the final batch volume of purified water (at 20 3 C) to the feed vessel, and pass through the microfluidizer operating at approximately 30,000 psi. Collect the rinse in the vessel containing the concentrate. Add approximately 22% of the final batch volume of purified water (20 3 C) to the vessel with the concentrate, and mix for approximately five (5) minutes. Add the remainder of the polysorbate 80 and simethicone, and mix for approximately five (5) minutes.

Add the sodium benzoate, sodium citrate and citric acid and mix for approximately five (5) minutes. Add the xanthan gum slowly with constant mixing.
Continue to mix after addition of the xanthan gum. Allow the xanthan gum to hydrate without mixing for 30 minutes. Add the glycerin with constant mixing.
Add the liquid glucose slowly with constant mixing. Mix for five minutes or until it is dissolved. Add the titanium dioxide and mix using a suitable homogenizer until that ingredient is fully dispersed. Add the artificial cherry flavor, and mix for approximately five minutes. Add purified water at 20 3 C, and qs up to a final volume, and mix until a uniform suspension is attained. Collect approximately 20 ml sample for pH measurement and physical observation of the suspension. The pH
of the suspension of Example 1 was 5Ø

Example 2 Example 2 is another example of a formulation within the scope of the present invention prepared using the procedure of Example 1 and has a pH of 4.5.
Ingredient Concentration (mg/ml) Posaconazole (micronized) 40 Polysorbate 80 10 Sodium Citrate, USP, 0.6 Monohydrate Citric Acid, USP, Monohydrate 1.5 Simethicone, USP 3 Xanthan Gum, NF 3 Sodium Benzoate, NF 2 Liquid Glucose, NF 350 Glycerin, USP 100 Artificial Cherry Flavor 5 Titanium Dioxide 4 Purified Water, USP q.s. ad 1 ml The rate of sedimentation of the liquid suspension of the present invention was determined as set forth below.

Posaconazole Oral Suspension 40 mg/ml Rate of Sedimentation Sodium Bottle Posaconazole % Label Benzoate % Label Number Time mg/ml Strength mg/mi Strength 1 0 min 39.9 99.8 2.00 100 1 5 min 40.0 100 1.99 99.5 1 10 min 40.0 100 2.00 100 1 30 min 40.0 100 2.00 100 1 60 min 40.2 101 2.01 101 1 3 days 40.2 101 2.02 101 2 0 min 39.8 99.5 2.01 101 2 5 min 39.9 99.8 2.00 100 2 10 min 40.2 101 2.01 101 2 30 min 39.8 99.5 1.99 99.5 2 60 min 40.2 101 2.02 101 2 3 days 40.1 100 2.01 101 Two bottles containing the suspension of the present invention were shaken 1o and left to rest. The bottles were then sampled immediately (time zero), then after 5 minutes, 10 minutes, 30 minutes, 60 minutes and after 72 hours (three days) post shaking. The levels of posaconazole and of the preservative (Sodium Benzoate) in these samples were assayed by HPLC. HPLC methods of detection are well-known to one of skill in the art.

The results of the assay of the preservative and of the posaconazole remained consistent and did not change. These ranged from 39.8 to 40.2 mg/ml (99.5 to 101 %) for the active and 1.99 to 2.02 mg/m: (99.5 to 101 %) for the preservative, respectively. The results of this experiment are shown in Table above.

The sodium benzoate was not expected to sediment. Surprisingly, the posaconazole was not sedimented after 3 days.

Thus, the compositions of the present invention have both ease of dispersibility and homogeneity as is evidenced by the stability of the samples in to Table 1.

Next, accelerated homogeneity testing was performed on the liquid suspension of the present invention.

Posaconazole Oral Suspension 40 mg/ml Homogeneity Accelerated Posaconazole Sodium Benzoate Condition Time point % Label Strength % Label Strength Initial Initial 103;102;104 105;102;103 30 H (30 C/60%RH) 3 Months 103;105;104 103;107;105 RH4 (40 C/75%RH) 3 Months 102;104;103 104;106;106 30 H 6 Months 102;101;102 103;101;102 RH4 6 Months 102;102;102 101;101;102 H 12 Months 104;104;104 101;100;100 25 H 24 Months 104;104;104 101;101;101 * Shaking and receiving the dose as per patient instruction.

These data (sedimentation rate experiment) were in agreement with the real 20 time stability data (up to 6 months at 40 C/75%RH and up to 24 months at 25 C/60%RH) that are shown in Table 2. The assay homogeneity results, surprisingly, remained consistently homogenous and practically unchanged.

After 6 months at 40 C/75%RH the homogeneity results ranged from 40.7 to 40.8 mg/mI (101 %) for the active and 2.01 to 2.03 mg/ml (101 to 102%) for preservative, respectively. These results were obtained regardless of the portion of the bottle assayed, i.e., top, or bottom of the bottle. Therefore, it can be concluded that the suspension was homogenous throughout the bottle even after relatively long exposure to accelerated stability conditions.

After 24 months at 25 C/60%RH the homogeneity results ranged from 41.5 1o to 41.6 mg/ml (104%) for the active and 2.01 mg/ml (101 %) for the preservative, respectively. These results were obtained regardless of the portion of the bottle assayed, i.e., top or bottom of the bottle. Therefore, it can be concluded that the suspension was homogenous throughout the bottle even after long term (24 months) exposure to 25 C/60%RH.

Bioavailability is defined as the rate and extent to that the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.

Cmax value is defined as the maximum concentration of the antifungal compound measured (i.e. "peak") in the plasma serum.

Formulations of the present invention have the advantage that they have an increased bioavailability and lower variability than previous formulations.

The relative bioavailability of the posaconazole oral suspension was compared to a solid dosage form of posaconazole in healthy subjects.

The first objective was to determine the relative bioavailability of posaconazole given as an oral suspension compared to an oral solid formulation when administered with a high-fat breakfast. The second objective was to determine the effect of high-fat and non-fat food relative to fasting conditions on the 5 oral bioavailability of the compound of formula I when given as an oral suspension.
Twenty healthy subjects completed this randomized, open-label, 4-way crossover, single-dose bioavailability and food effect study of posaconazole.
Subjects received each of the following four treatments separated by at least a 7 day washout period:

Treatment A: 200 mg of the compound of formula I in the oral suspension of this invention (5 ml) following a 10-hr.
fast Treatment B: 200 mg of the compound of formula I in the oral suspension of this invention (5 ml) with a standardized high-fat breakfast Treatment C: 200 mg of the compound of formula I in the oral suspension of this invention (5 ml) with a standardized non-fat breakfast Treatment D: 2 x 100 mg of the compound of formula I in the tablets (co-precipitate formulation of U.S. Patent No. 5,834,472 with a standardized high-fat breakfast Subjects were randomized to either remain fasted (Treatment A), to receive a standardized high fat breakfast (Treatment B or D) or a standardized non-fat breakfast (Treatment C). Meals were consumed in a 20-minute period prior to the morning drug administration and subjects received the appropriate treatment within 5 minute of completing the breakfast.

Blood samples (6 ml) were collected into heparinized tubes for each treatment immediately prior to dosing (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours after dosing. Blood was centrifuged at 4 C and plasma stored at or below -20 C until assayed. Plasma concentrations of posaconazole were assayed using a validated high performance liquid chromatographic assay with a LOQ of ng/ml.

Individual plasma concentration-time data were used for pharmacokinetic analysis using model-independent methods. The maximum concentration (Cmax) and time of maximum concentration (Tmax) were the observed values. The area to under the plasma concentration-time curve from time zero to the final quantifiable sampling time [AUC(tf)] was calculated using the linear trapezoidal method and extrapolated to infinity (I) as follows:

C(tf) AUC(I) = AUC(tf) K

where C(tf) is the estimated concentration determined from linear regression at time, tf.

Total body clearance was calculated by the following:
CL =Dose/ AUC(I) The apparent volume of distribution (Vdarea/F) was calculated from the ratio of the total body clearance to the terminal phase rate constant (K).

Summary statistics were calculated for the plasma suspension formulation of the present invention compared to a prior art tablet formulation concentration-time data at each time point and the derived pharmacokinetic parameters. The original scale and log-transformed Cmax and AUC values were analyzed using an analysis of variance (ANOVA). The effects due to subject, phase and treatment were extracted.

The plasma concentration-time data and pharmacokinetic parameters for the compound of formula I are tabulated in Tables 3 & 4 and depicted graphically in Figures 1 & 2.

All subjects had 0-hour concentrations on Day 1 reported as below the LOQ
(5 ng/ml) except for Subject 20 in Phases 3 and 4 who had quantifiable levels of posaconazole at 0-hour for Treatments B and A of 8.5 and 22.5 ng/ml, respectively.

io These levels are most likely due to a carry-over effect from accumulation from previous doses.

A summary of the meana pharmacokinetic parameters are provided in the table below:

Table 3 Tablet Suspension High Fat D 10 hr Fast A High Fat B Non-Fat C
Parameter Unit Mean %CV Mean %CV Mean %CV Mean %CV
Cmax ng/ml 413 33 132 50 512 34 378 43 Tmax Hr 5.5 32 5.01 49 4.8 9 4.1 21 AUC(tf) ng-hr/ml 10304 41 3553 36 13885 41 9511 38 AUC(I) ng-hr/ml 11832 39 4179 31 15059 26 10753 35 t%2 hr 21.0 15 23.5 25 23.0 19 22.2 18 a: Balanced means, n=20 except for AUC(I) and t'/2, n=1 5.

Posaconazole was slowly absorbed; the mean Tmax values ranged from 4.1 to 5.5 hr. Posaconazole was slowly eliminated with a mean terminal t1/2 of about 22 hour which was independent of treatment. This study was conducted to evaluate the bioavailability of posaconazole oral suspension (Treatment B) compared to a tablet formulation (Treatment D), both given with a high-fat food. The results, based on log-transformed data, are shown below:

Table 4 Treatments Relative 90%
Given After Bioavailability Confidence High Fat Geometric b Interval Parameter Breakfast Mean (%) Cmax Suspension 485 ng/ml 123.3 104-146 Tablet 394 ng/ml a Suspension 13141 ng.hr/ml 136.5 119-156 AUC(tf) Tablet 9624 ng.hr/ml a: AUC(tf) was used for statistical comparisons because it could be calculated for all treatments for all subjects.
b: Suspension relative to tablet.

On average, the suspension formulation of the present invention resulted in 1o a 23% increase in Cmax and a 36% increase in AUC(tf) compared to the tablet of the prior art.

The secondary objective of the study was to evaluate the effect of high fat food (Treatment B) and non-fat food (Treatment C) compared to fasting (Treatment A) on the oral bioavailability of posaconazole administered as an oral suspension.

The results, based on log-transformed data, are shown below:

Table 5 Relative Bioavailability 90%
Suspension Geometric a Confidence Parameter Treatments Mean (%) Interval Cmax High-Fat 485 417 352-493 (ng/ml) Non-Fat 345 296 250-350 Fast 116 -- --AUC(tf) High-Fat 13141 392 343-448 (ng.hr/ml Non-Fat 8857 264 231-302 Fast 3352 -- --a: Expressed as a percent of Treatment A - Suspension/Fast.

A high fat breakfast produced a 4-fold increase in the bioavailability of posaconazole given in a suspension. This was consistent with results from a previous study where food significantly increased the bioavailability of posaconazole by 3-5-fold for both tablet and capsule formulations. The effect of a non-fat breakfast (Treatment C) compared to fasting (Treatment A) was less, with a 2.5-3-fold increase in bioavailability.

Many modifications and variations of this invention can be made without io departing from its spirit and scope, as will be apparent to one skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMS:

1. A liquid suspension comprising an antifungally effective amount of the micronized compound represented by the chemical structural formula I:

wherein the micronized compound of formula I has a mean particle size of about 1000 nm to about 1800 nm, at least one thickening agent, at least one non-ionic surfactant, and a pharmaceutically acceptable liquid carrier.

2. The liquid suspension of claim 1, wherein the at least one non-ionic surfactant is a block copolymer of ethylene oxide and propylene oxide, glycol or glyceryl esters of saturated or unsaturated C8 to C20 acids, polyoxyethylene esters of saturated or unsaturated C8 to C20 acids, polyoxyethylene ethers of saturated or unsaturated C8 to C20 acids or polyvinylalcohols or sorbitan esters of saturated or unsaturated C10 to C20 acids.

3. The liquid suspension of claim 1, wherein the at least one non-ionic surfactant is a polyoxyethylene derivative of a sorbitan ester of a saturated or unsaturated C10 to C20 acid.

4. The liquid suspension of claim 1, wherein the at least one thickening agent is selected from the group consisting of xanthan gum, liquid sugars, starches, celluloses, and mixtures of two or more thereof.

5. The liquid suspension of claim 1, wherein a combination of xanthan gum and a liquid sugar is used as the at least one thickening agent.

6. The liquid suspension of claim 1, wherein the micronized compound of formula I has a mean particle size of about 1200 nm to about 1600 nm.

7. The liquid suspension of claim 1, comprising an amount of a buffer system effective to maintain the pH of the system in the range of about 4.0 to about 6Ø

8. The liquid suspension of claim 7, wherein the at least one non-ionic surfactant is a polyoxyethylene derivative of a sorbitan ester of a saturated or unsaturated C10 to C20 acid.

9. The liquid suspension of claim 8, wherein the sorbitan ester is one or more fatty acid ester of sorbitan selected from the group consisting of sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate and sorbitan tristearate.

10. The liquid suspension of claim 7, wherein the at least one thickening agent is selected from the group consisting of gums, liquid sugars, starches, celluloses, and mixtures of two or more thereof.

11. The liquid suspension of claim 7, wherein a combination of a xanthan gum and a liquid sugar is used as the at least one thickening agent.

12. The liquid suspension of claim 7, wherein a combination of a xanthan gum and a liquid glucose is used as the thickening agent.

13. The liquid suspension of claim 7, wherein the buffer system comprises sodium citrate and citric acid.

14. The liquid suspension of claim 7, wherein the pharmaceutically acceptable liquid carrier is a combination of purified water, glucose, and glycerin.

15. The liquid suspension of claim 7, wherein the micronized compound of formula I has a mean particle size of about 1200 nm to about 1600 nm.

16. The liquid suspension of claim 1, comprising:

a non-ionic surfactant which is a polyoxyethylene derivative of sorbitan esters of saturated or unsaturated C12 to C18 acids, a combination of two thickening agents, wherein one is a liquid sugar, and an effective amount of a buffer system sufficient to maintain a pH in the range of about 4.0 to about 6Ø

17. The liquid suspension of claim 16, wherein the micronized compound of formula I has a mean particle size in the range of about 1200 nm to about 1600 nm.

18. A liquid suspension of claim 1 wherein the at least one thickening agent is xanthan gum.

19. The liquid suspension of claim 1, wherein the at least one non-ionic surfactant, is polyoxyethylene sorbitan monooleate.

20. The liquid suspension of claim 1, wherein the thickening agent is xanthan gum and a liquid sugar, and the non-ionic surfactant is a polyoxyethylene sorbitan monooleate.

21. The liquid suspension of claim 16, comprising a buffer system effective to maintain the pH of the system in the range of 4.0 to 6Ø

22. The liquid suspension of claim 21, wherein the buffer system comprises sodium citrate and citric acid.

23. A composition for at least one of treating and preventing a fungal infection in a patient, the composition in the form of a liquid, oral suspension comprising an antifungally effective amount of micronized particles of the compound of formula I:

wherein the micronized compound of formula I has a mean particle size of 1000 nm to 1800 nm, and the composition comprises at least one thickening agent, at least one non-ionic surfactant, and a pharmaceutically acceptable liquid carrier.

24. The composition of claim 23, wherein the suspension is adapted to provide a maximum concentration (Cmax) of posaconazole in the plasma serum of 485 ng/ml to 512 ng/ml post-single dose administration.

25. The composition of claim 24, wherein the Cmax is measured at a time of maximum concentration (Tmax) in the range of 4 to 5 hours post-single dose administration.

26. The composition of claim 24, wherein a plot of the plasma concentration of posaconazole over time yields an Area Under the Curve over 72 hours [AUC(O-72 hrs)] value of posaconazole of 13141 ng-hr/ml to 13885 ng-hr/ml.

27. The composition of claim 24, wherein the Cmax of posaconazole is 485 ng/ml, and an Area Under the Curve over 72 hours [AUC(O-72 hrs)] value of posaconazole is 13141 ng-hr/ml.

28. The composition of claim 24, wherein the Cmax of posaconazole is 512 ng/ml, and an Area Under the Curve over 72 hours [AUC(O-72 hrs)] value of posaconazole is 13885 ng-hr/ml.

29. The composition of claim 24, wherein said liquid, oral suspension is adapted for administration with a high-fat meal to deliver 200 mg of posaconazole.

30. A composition for at least one of treating and preventing a fungal infection in a patient, the composition in the form of a liquid, oral suspension comprising an antifungally effective amount of a micronized compound of the chemical structural formula I:

wherein the micronized compound of formula I has a mean particle size of 1000 nm to 1800 nm, and the composition comprises at least one thickening agent, at least one non-ionic surfactant, and a pharmaceutically acceptable liquid carrier, and is adapted to provide a maximum concentration (Cmax) of posaconazole in the plasma serum that is 2.5 to 4 times greater when administered with a high-fat meal or a non-fat meal as compared to when administered following a 10 hr fast.

31. The composition of claim 30, wherein the Cmax of posaconazole in the plasma serum is 4 times greater when administered with a high-fat meal as compared to when administered following a 10 hr fast.

32. The composition of claim 31, wherein said liquid, oral suspension is adapted for administration to deliver 200 mg of posaconazole.

33. Use of micronized particles of the compound of formula I

in the manufacture of a medicament in the form of a liquid, oral suspension for at least one of treating and preventing a fungal infection in a patient comprising an antifungally effective amount of the compound of formula I, wherein the medicament comprises at least one thickening agent, and least one surfactant and a pharmaceutically acceptable liquid carrier, wherein the micronized compound of formula I has a mean particle size of about 1000 nm to about 1800 nm.

34. The use of the liquid suspension as defined in claim 1, wherein the suspension is adapted to provide a maximum concentration (Cmax) of posaconazole in the plasma serum of about 485 ng/ml to about 512 ng/ml post-single dose administration.